It has been reported that blood lipids, especially cholesterol and triglycerides, are closely related to various kind of diseases such as coronary cardio-circulatory diseases, e.g., arteriosclerosis and hypercholesterolemia, and fatty liver. Cholesterol, a fatty steroid alcohol, is a blood lipid produced from saturated fat in the liver. Triglycerides are another type of blood lipids which are known to increase the risk of various diseases. It has also been reported that an elevated blood or plasma cholesterol level causes the deposition of fat, macrophages and foam cells on the wall of blood vessels, such deposit leading to plaque formation and then to arteriosclerosis (see Ross, R., Nature, 362, 801-809 (1993)). One of the methods for decreasing the plasma cholesterol level is alimentotherapy to reduce the ingestion of cholesterol and lipids. Another method is to inhibit the absorption of cholesterol by inhibiting enzymes involved therein.
Acyl CoA-cholesterol-o-acyltransferase (ACAT) promotes the esterification of cholesterol in blood. Foam cells are formed by the action of ACAT and contain a large amount of cholesterol ester carried by low density lipoprotein (LDL) in the blood. The formation of foam cells on the wall of artery increases with the ACAT activity, and, accordingly, an inhibitor of ACAT may also be an agent for preventing arteriosclerosis. Further, it has been reported that the blood level of LDL-cholesterol can be reduced by inhibiting the ACAT activity (see Witiak, D. T. and D. R. Feller (eds.), Anti-Lipidemic Drugs: Medicinal, Chemical and Biochemical Aspects, Elsevier, pp159-195 (1991)).
Further, it has been reported that hypercholesterolemia can be treated effectively by reducing the rate of cholesterol biosynthesis through the inhibition of cholesterol ester transfer protein (CETP) which mediates the cholesterol transfers between the lipoproteins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which mediates the synthesis of mevalonic acid, an intermediate in the biosynthesis of sterols or isoprenoids (see Cardiovascular Pharmacoloqy, William W. Parmley and Kanu Chatterjee Ed., Wolfe Publishing, pages 8.6-8.7, 1994).
Therefore, numerous efforts have been made to develop medicines to inhibit HMG-COA reductase; and, as a result, several compounds derived from Penicillium sp. and Aspergillus sp. have been commercialized. Specifically, Lovastatin.RTM. and Simvastatin.RTM. developed by Merck Co., U.S.A., and Pravastatin.RTM. developed by Sankyo Co., Japan, have been commercialized (see C. D. R. Dunn, Stroke: Trends, Treatment and Markets, SCRIPT Report, PJB Publications Ltd., 1995).
However, these medicines are very expensive and a long-term administration thereof is known to induce an adverse side effect in the central nervous system. Further, although Lovastatin.RTM. and Simvastatin.RTM. may reduce the plasma LDL cholesterol level by enhancing the activity of LDL receptor in the liver, they cause side effects such as increase in creatine kinase in the liver and rhabdomyolysis (see Farmer, J. A., et al., Baillers-clin. Endocrinol. Metal., 9, 825-847 (1995)). Accordingly, there has continued to exist a need to develop an inexpensive and non-toxic inhibitor of HMG-COA reductase.
Another example of the elevated blood-lipid level-related disease is fatty liver which is causes by excessive intake of fat-containing foods and alcohol. When afflicted by fatty liver, a large amount of lipids is deposited in the liver tissue and the levels of serum GOT (glutamate-oxaloacetate transaminase), GPT (glutamate-pyruvate transaminase) and .gamma.-GTP (.gamma.-glutamyl transpeptidase) become elevated (see T. Banciu et al., Med. Interne., 20, 69-71 (1982); and A. Par et al., Acta. Med. Acad. Sci. Hunq., 33, 309-319 (1976)). In the process of developing fatty liver, fat accumulates in the liver mainly in the form of triglycerides and fatty acids, and also to a minor extent, in the form of cholesterol. Further, it has been reported that one of the major signs of fatty liver is high blood cholesterol and/or triglyceride contents. Therefore, fatty liver is closely related to the level of cholesterol and/or triglycerides in the blood.
Hayashi et al. has reported that an extract from green tea improved liver function in a rat by preventing the elevation of serum GOT and GPT (M. Hayashi et al., Nippon Yakuri gaku Zasshi, 100, 391-399 (1992)).
It has been reported that the phenolic compounds which exist in the natural world, especially in vegetables and fruits exhibit various useful pharmacological activities against anti-cancer, virus and lipid oxidation and also in preventing circulatory diseases.
The present inventors have endeavored to develop a novel pharmacological use of phenolic compounds which are abundantly present in vegetables and fruits. As a result, it has been discovered that tannin, gallic acid and ellagic acid are effective in treating or preventing elevated blood lipid level-related diseases. Specifically, it can greatly reduce plasma cholesterol level; prevent the activities of HMG-COA reductase and ACAT; inhibit the accumulation of macrophage-lipid complex on the endothelial wall of an artery; and prevent hepatic dysfunctions in a mammal.